The EU-OPENSCREEN fragment library

A well-curated fragment library is usually the starting point for fragment-based lead discovery, and not an insignificant investment. If you are just starting out you may want to use an existing library. One such option is described in an (open-access) paper in RSC Med. Chem. by Jordi Mestres and collaborators at IMIM Hospital del Mar Medical Research Institute and across Europe.

 

The EU-OPENSCREEN European Research Infrastructure Consortium (ERIC) allows researchers to access early lead discovery and chemistry resources. Among other components, it includes a set of more than 96,000 compounds for high-throughput screening, the European Chemical Biology Library, or ECBL. To complement this, the researchers have developed what they call the European Fragment Screening Library, or EFSL.

 

Recognizing that rapid follow-up is a critical next step in fragment-based lead discovery, the researchers designed EFSL based on ECBL. They did this by choosing fragments commercially available from Enamine that were sub-structures of ECBL members. Fragments were chosen to represent as much of the ECBL as possible, as well as for rule-of-three compliance. Fragments with multiple vectors for growing were also prioritized, similar to the “sociable fragments” concept we wrote about here. Finally, a set of 88 very small “minifrags” were also included.

 

Fragments were dissolved in deuterated DMSO at 100 mM (or 1000 mM for minifrags). Solubility and integrity were assessed at 1 mM (or 10 mM for minifrags) in PBS using ¹H-NMR using an internal standard; those with solubility < 0.2 mM were rejected, as were those with missing or extra peaks in the NMR spectra. Of 1056 compounds tested, 913 passed these QC criteria.

 

The EFSL is available for screening (via grant applications), and the paper summarizes the results of eight screens performed over two years using a range of detection technologies including crystallography, ligand-detected NMR, small-angle X-ray scattering, thermal shift, and BLI. Hit rates ranged form just 0.1% to 31.3%, though in the last case only a small subset of the library was tested.

 

After fragment screening and confirmation, four of the projects tested larger compounds from the ECBL in follow-up studies, and two were able to identify hits. One project targeting a bacterial beta-ketoacyl-ACP synthase 2 (FabF) used BLI to identify a fragment with a dissociation constant of 35 µM. Of the 147 compounds related compounds from the ECBL, two had slightly higher affinity, albeit at the expense of lower ligand efficiency. Perhaps exploring Enamine REAL Space as in this example would be more effective at finding significantly more potent molecules.

 

In summary, the EFSL seems to be a useful resource, particularly for academic labs. If you’ve got a target and no internal fragment-screening capabilities, it might be worth putting in an application.